U.S. patent number 5,588,556 [Application Number 08/461,871] was granted by the patent office on 1996-12-31 for method for generating gas to deliver liquid from a container.
This patent grant is currently assigned to River Medical, Inc.. Invention is credited to Mark C. Doyle, Frederic P. Field, Gregory E. Sancoff.
United States Patent |
5,588,556 |
Sancoff , et al. |
December 31, 1996 |
**Please see images for:
( Certificate of Correction ) ** |
Method for generating gas to deliver liquid from a container
Abstract
The present invention relates to chemical reactants,
compositions, methods to manufacture reactants, and apparatus for
the generation of a gas pressure to drive a fluid from an infusion
pump at controlled flow rates.
Inventors: |
Sancoff; Gregory E. (Rancho
Santa Fe, CA), Doyle; Mark C. (San Diego, CA), Field;
Frederic P. (Solana Beach, CA) |
Assignee: |
River Medical, Inc. (San Diego,
CA)
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Family
ID: |
22764014 |
Appl.
No.: |
08/461,871 |
Filed: |
June 5, 1995 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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205875 |
Mar 3, 1994 |
5398850 |
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105327 |
Aug 6, 1993 |
5398851 |
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105284 |
Aug 6, 1993 |
5397303 |
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Current U.S.
Class: |
222/1; 222/394;
222/396 |
Current CPC
Class: |
A61M
5/14593 (20130101); A61M 5/1483 (20130101); A61M
5/155 (20130101); B01J 7/02 (20130101); B65D
83/625 (20130101); A61M 5/1409 (20130101); A61M
2005/1404 (20130101); A61M 2005/14204 (20130101) |
Current International
Class: |
A61J
1/00 (20060101); A61M 5/145 (20060101); B01J
7/02 (20060101); B01J 7/00 (20060101); B65D
83/14 (20060101); A61M 5/142 (20060101); B05B
11/00 (20060101); B65D 083/14 () |
Field of
Search: |
;222/1,386,386.5,394,396,397,399,389 ;604/145 ;239/322,323
;169/33,85 ;424/44 ;422/305 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0509335A1 |
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Oct 1992 |
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EP |
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2687291 |
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Aug 1993 |
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FR |
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1270781 |
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Apr 1972 |
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GB |
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WO9207612 |
|
May 1992 |
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WO |
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WO9325269 |
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Dec 1993 |
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WO |
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Primary Examiner: Shaver; Kevin P.
Attorney, Agent or Firm: Knobbe, Martens, Olson &
Bear
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a divisional of U.S. patent application Ser.
No. 08/205,875 filed Mar. 3, 1994, now U.S. Pat. No. 5,398,850,
which is a continuation-in-part of U.S. patent application Ser. No.
08/105,327 filed Aug. 6, 1993, now U.S. Pat. No. 5,398,851 and
application Ser. No. 08/105,284 filed Aug. 6, 1993, now U.S. Pat.
No. 5,397,303, the disclosure of which is hereby incorporated by
reference.
Claims
What we claim is:
1. In an apparatus for the delivery of a liquid from a container,
of the type wherein the apparatus includes a first and a second
chemical, the first and second chemical being reactive to generate
carbon dioxide gas, with the first chemical being disposed in solid
form and the second chemical being disposed as a liquid, the
improvement comprising:
the first chemical being admixed with a rate limiting amount of a
rate controlling moiety and formed into a solid mass.
2. A method to generate carbon dioxide gas for the controlled
delivery of a liquid from a container, comprising:
providing a first and a second chemical, said first and second
chemicals being reactive to generate carbon dioxide gas upon
contact therebetween at a substantially constant rate, said
chemicals being initially separated from one another;
allowing said first and second chemicals to come into contact and
react to generate the gas; and
communicating said gas to means operative to drive the liquid from
the container,
wherein, the gas generating reaction is continued for a sufficient
length of time to deliver the liquid from the container and the
liquid is driven from the container at a substantially constant
flow rate.
3. A method to generate carbon dioxide gas for the controlled
delivery of a liquid from a container, comprising:
providing an alkali metal carbonate formed into a tablet and a
liquid chemical that is reactive with the carbonate to generate
carbon dioxide gas, said chemicals being initially separated from
one another, and wherein said tablet is at least partially coated
with a barrier that is at least partially insoluble in the liquid
chemical;
allowing said first and second chemicals to come into contact and
react to generate the gas at a substantially constant rate; and
communicating said gas to means operative to drive the liquid from
the container at a substantially constant flow rate.
4. A method to generate carbon dioxide gas for the controlled
delivery of a liquid from a container, comprising:
providing a first and a second chemical, said first and second
chemicals being reactive to generate a gas upon contact
therebetween, said chemicals being initially separated from one
another;
allowing said first and second chemicals to come into contact and
react to generate a gas such that upon attainment of the
predetermined pressure within the first container, the container is
maintained at said predetermined pressure through pressure
maintenance means; and
communicating said gas to means operative to drive a liquid from
said container at a substantially constant flow rate.
5. The method of claim 4, wherein said pressure maintenance means
is a pressure relief valve in fluid communication with said
container.
6. The method of claim 4, further comprising controlling the
reaction rate between said first and second chemicals by admixing
au least one of said chemicals with a rate limiting amount of a
rate controlling moiety.
7. The method of claim 4, wherein said second chemical is a liquid
and said first chemical is a tablet at least partially coated with
a barrier that is at least partially insoluble in the liquid
chemical, and said method further comprises controlling the
reaction rate between said first and second chemicals by the amount
of barrier coated onto said tablet.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to chemical reactants, compositions,
methods to manufacture reactants, and apparatus for the generation
of a gas pressure to drive a fluid from an infusion pump.
2. Background of the Art
There are several examples in the art of infusion pumps which
operate on the use of gas pressure to drive an infusion liquid into
a patient. For example, in Baron, U.S. Pat. No. 4,379,453, an
infusion bag is equipped with an internal bag including a set of
reactive chemicals that when mixed react to form a gas and inflate
the internal bag to drive a liquid from the infusion bag.
Similarly, in Baron, U.S. Pat. No. 4,379,453 the inventor disposed
the reactive chemicals into a cuff-like apparatus to squeeze the
liquid from the infusion bag.
The use of gas pressure, without the need for a chemical reaction,
has also been demonstrated. See U.S. Pat. No. 5,106,374.
However, in each of the above-described patents, there is a limited
ability for an operator to control the pressure of the gas and
ultimately the flow rate of the liquid from the device. Baron in
U.S. Pat. No. 4,379,453 attempted to solve this problem by
utilizing a plurality of reactions. However, this system merely
creates two "peaks" in pressure and consequently flow rate.
Accordingly, a need exists in the art for controlled rate infusion
devices which can be retrieved through the use of reactive
chemicals to generate gas.
SUMMARY OF THE INVENTION
The present invention solves the foregoing problem in the art
through the provision of particular chemical reactants,
compositions of the chemical reactants, methods to manufacture the
chemical reactants, and apparatus that allow for the controlled
generation of a gas in, and consequently the flow rate of a liquid
from an infusion pump.
In accordance with a first aspect of the present invention there is
provided a composition for use in a carbon dioxide generating
reaction, comprising an alkalai metal carbonate admixed with a rate
limiting amount of a rate controlling moiety and formed into a
solid mass. In a preferred embodiment, the alkalai metal carbonate
is selected from the group consisting of sodium carbonate,
magnessium carbonate, and calcium carbonate. In another preferred
embodiment, the rate controlling moiety is selected from the group
consisting of polyvinylpyrrolidone, polyethylene glycol, polyvinyl
alcohol croscarmellose sodium. Preferably, the mass is partially
coated with a material that is nonreactive with a liquid chemical
that is reactive with the carbonate to form carbon dioxide.
Moreover, preferably, the material is also insoluble in the liquid
chemical. In a highly preferred embodiment, the mass is reacted
with an effective amount of water to enhance the mechanical
properties and hardness of the mass.
In accordance with a second aspect of the present invention, there
is provided an apparatus for the generation of a gas to push a
liquid from a container, comprising a substantially closed housing
having an outside wall in fluid communication with the container,
the housing further comprising and separately enclosing an alkalai
metal carbonate formed into a solid mass and a liquid chemical that
is reactive with the carbonate to form carbon dioxide gas, and
means for combining the carbonate and the liquid chemical.
Preferably, the alkalai metal carbonate is selected from the group
consisting of sodium carbonate, magnesium carbonate, and calcium
carbonate. Also, preferably, the liquid chemical is selected from
the group consisting of solutions of citric acid and acetic acid.
In a preferred embodiment, the mass further comprises a rate
limiting amount of a rate controlling moiety admixed with the
carbonate. In another preferred embodiment, the mass is partially
coated with a material that is nonreactive with a liquid chemical
that is reactive with the carbonate to form carbon dioxide.
Preferably, the material is also insoluble in the liquid chemical.
In a highly preferred embodiment, the mass is reacted with an
effective amount of water to enhance the mechanical properties and
hardness of the mass. In a preferred embodiment, the combining
means comprises a frangible member that is adapted to be pierced
upon an application of a force through the outside wall of the
housing.
In accordance with a third aspect of the present invention, there
is provided an apparatus for the generation of a gas to push a
liquid from a container, comprising a hydrophobic membrane
surrounding and separately enclosing an alkalai metal carbonate
formed into a solid mass and a liquid chemical that is reactive
with the carbonate to form carbon dioxide gas, the hydrophobic
membrane being positioned in gas communication with the container,
and means for combining the carbonate and the liquid chemical. In a
preferred embodiment, the alkalai metal carbonate is selected from
the group consisting of sodium carbonate, magnessium carbonate, and
calcium carbonate. In another preferred embodiment, the liquid
chemical is selected from the group consisting of solutions of
citric acid and acetic acid. In a preferred embodiment, the mass
further comprises a rate limiting amount of a rate controlling
moiety admixed with the carbonate. In another preferred embodiment,
the mass is partially coated with a material that is nonreactive
with a liquid chemical that is reactive with the carbonate to form
carbon dioxide. The material is preferably also insoluble in the
liquid chemical. In another preferred embodiment, the mass is
reacted with an effective amount of water to enhance the mechanical
properties and hardness of the mass. In another preferred
embodiment, the combining means comprises a frangible member that
is adapted to be pierced upon an application of a force through the
outside wall of the membrane.
In accordance with another aspect of the present invention, there
is provided an improvement in an apparatus for the delivery of an
infusion liquid from a container, of the type wherein the apparatus
separately includes a first and a second chemical, the first and
second chemical being reactive to generate carbon dioxide gas, with
the first chemical being disposed in solid form and the second
chemical being disposed as a liquid, the improvement comprising the
first chemical being admixed with a rate limiting amount of a rate
controlling moiety and formed into a solid mass.
In accordance with another aspect of the present invention, there
is provided a method to generate carbon dioxide gas for the
controlled delivery of a liquid from a container, comprising
separately providing a first and a second chemical, at least one of
the chemicals enclosed in a first container, the first and second
chemicals being reactive to generate carbon dioxide gas upon
contact therebetween, providing means for controlling the reaction
rate between the first and second chemicals, and means operable to
allow the chemicals to come into contact with one another,
activating the contact means so that the first and second chemicals
come into contact and react to generate the gas, and communicating
the gas to means operative to drive the liquid from the second
container, wherein, the controlling means acts to continue the
reaction for a sufficient length of time to deliver the liquid from
the container and the liquid is driven from the container at a
substantially constant flow rate.
In accordance with another aspect of the present invention, there
is provided a method to generate carbon dioxide gas for the
controlled delivery of a liquid from a container, comprising
separately providing a first and a second chemical, at least one of
the chemicals enclosed in a first container, the first and second
chemicals being reactive to generate a gas upon contact
therebetween, providing means operable to allow the chemicals to
come into contact with one another, and means operable to maintain
a predetermined pressure, activating the contact means so that the
first and second chemicals come into contact and react to generate
a gas such that upon attainment of the predetermined pressure
within the first container, the container is maintained at the
predetermined pressure through the pressure maintenance means, and
communicating the gas to means operative to drive a liquid from a
second container at a substantially constant flow rate.
In accordance with another aspect of the present invention, there
is provided an improvement in a method to manufacture an apparatus
for the delivery of an infusion liquid from a container, the
apparatus being of the type wherein a first and a second chemical
are separately included, the first and second chemical being
reactive to generate carbon dioxide gas, with the first chemical
being disposed in solid form and the second chemical being disposed
as a liquid, the improvement comprising sterilizing the apparatus
with heat.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
FIG. 1. is a top perspective view of a preferred solid reactant
tablet in accordance with the invention.
FIG. 2. is a top perspective view of a preferred solid reactant
tablet coated with an insoluble sealant in accordance with the
invention.
FIG. 3. is a cross-sectional view of the tablet in FIG. 2 along
line 3--3 that is partially reacted.
FIG. 4. is a top perspective view of a preferred solid reactant
tablet coated with an insoluble sealant in accordance with the
invention.
FIG. 5. is a cross-sectional view of the tablet in FIG. 4 along
line 5--5 that is partially reacted.
FIG. 6. is a top perspective view of a preferred solid reactant
tablet coated with an reaction slowing coating with a portion of
the tablet cut away to show the variable thickness of the coating
on the tablet in accordance with the invention.
FIG. 7. is a cross-sectional side view of a preferred device that
operates and provides a reaction rate controlling environment in
accordance with the present invention.
FIG. 8. is a cross-sectional side view of the device in FIG. 7
showing the mode of operation.
FIGS. 9a and 9b are schematic cross-sectional views of a pressure
relief valve in accordance with the invention.
FIG. 10. is a graph showing the substantially linear flow rate
profile generated in accordance with the present invention in
comparison to reactions operated with the control features of the
present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In accordance with the invention, there are provided chemical
reactants, compositions of the chemical reactants, methods to
manufacture chemical reactant compositions, and apparatus to ensure
the controlled generation of a gas from a gas generating reaction
in order to provide a substantially constant flow rate of a liquid
from an infusion pump. In general, infusion pumps in which the
present invention is particularly useful are disclosed in copending
U.S. patent application, Ser. Nos. 08/105,327 and 08/105,284, the
disclosures of which are hereby incorporated by reference. The
infusion pumps disclosed therein generally include a housing
divided into a liquid reservoir and a gas expansion reservoir with
a membrane disposed therebetween. The membrane ordinarily extends
substantially into the gas expansion reservoir when the pump is
filled with a liquid in the liquid reservoir. Thus, when gas
expands within the gas expansion reservoir, the membrane is pushed
into the liquid reservoir, displacing liquid. In a preferred
embodiment, the gas expansion reservoir is in communication with a
gas generation reactor. The gas generation reactor separately
houses the reactive chemicals.
As will be appreciated, the control aspects of the present
invention are equally applicable with respect to other infusion
pump designs and would be expected to operate more effectively than
previous designs.
Chemical Reactants
In accordance with the present invention, there are provided
chemical reactants that are used effectively to generate a gas to
push a fluid from an infusion pump. In order to generate carbon
dioxide, two or more reactive chemicals are mixed that upon
reaction generate a gas. Preferably, one of the reactants is
provided in liquid form, i.e., a liquid chemical, a solution, or
the like, and another one of the reactants is provided as a solid.
Either the liquid or the solid may comprise more than one reactive
chemical. However, for simplicity, often, each of the liquid and
the solid contain only one reactive species.
Preferably, the gas generated is carbon dioxide. Carbon dioxide is
generally quite inert and safe at low concentrations. However,
other gases could also be used, provided they are relatively inert
and safe.
For the purposes of the following discussion, it will be assumed
that carbon dioxide is to be generated. As mentioned above, to
generate the gas, at least two reactants are caused to come into
contact. For ease of reference, the reactants will be referred to
herein as a first reactant and a second reactant or a solid
reactant and a liquid reactant and, particular sets of reactants
will be referred to as reactant sets.
First Reactant
Preferably, the first reactant is selected from the group
consisting of carbonates and bicarbonates, particularly, Group I
and II metal carbonates and bicarbonates (the "carbonate"). For
example, preferred carbonates include sodium bicarbonate, sodium
carbonate, magnesium carbonate, and calcium carbonate. However,
sodium bicarbonate, sodium carbonate and calcium carbonate are
highly preferred, with sodium carbonate (or soda ash) being the
most highly preferred. A desirable feature of sodium carbonate is
that it is easily sterilizable. For example, sodium carbonate can
be sterilized with heat, such as through autoclaving. This is
preferable, since the infusion devices for use with the invention
are designed for animal use and it is safer to ensure that all of
the components are sterile whether it is expected that they will
come into contact with the patient or not. Other reactants that are
sterilizable with heat are equally useful.
The carbonate can be either used as a solid reactant or can be
dissolved in a solution to form a liquid reactant. In a preferred
embodiment, the carbonate is used as a solid. The reason for this
choice is that the carbonates are all solids and some are only
sparingly soluble in water.
Second Reactant
The second reactant is preferably an acid. Preferably, the acid is
selected from the group consisting of acids, acid anhydrides, and
acid salts. Preferably, the second reactive chemical is citric
acid, acetic acid, acetic anhydride, or sodium bisulfate.
Usually the second reactant is used as the liquid reactant.
However, in the case of citric acid and sodium bisulfate, for
example, the second reactant can also be the solid reactant.
Nevertheless, generally the second reactant is more soluble in
water than the first reactant and is, therefore, used to form the
liquid reactant.
Reactant Sets
A reactant set is based upon a variety of considerations. For
example, the solubility of the first and second reactants are
considered to determine which reactant should be used as the solid
or liquid reactant. Also considered is the product of the reaction
and its solubility. It is preferred that the products be CO.sub.2
gas and a soluble inert compound. Once these factors are
considered, appropriate reactant sets can be constructed. For
instance, as will be appreciated, in preferred embodiments,
reaction sets such as those shown in Table I are preferred:
TABLE I ______________________________________ Solid Reactant
Liquid Reactant ______________________________________ Sodium
Carbonate Citric Acid Calcium Carbonate Acetic Acid Magnesium
Carbonate Citric Acid ______________________________________
Once the appropriate reactant sets are established, it is important
to determine the operating parameters that will be necessary to
control the generation of the gas and, therefore, provide a
substantially constant flow rate. As will be appreciated, the mere
reaction of the solid reactant as a powder and the liquid reactant
in the above reactant sets in the atmosphere at standard
temperature and pressure, will liberate gas at the maximum kinetic
rate for the reaction.
When enclosed under some pressure and under a CO.sub.2 atmosphere,
the kinetics will be slowed. Nevertheless, a flow rate of a liquid
driven from a pump by the gas, upon reaction of the first and
second reactants without any other control, will not be
substantially constant. Rather, the flow will initiate, increase
rapidly, level off, and then subside.
Accordingly, we unexpectedly discovered that through the
introduction of certain control parameters, the rate of generation
of a gas can be controlled and the flow rate from an infusion pump
can be maintained at a substantially constant rate. The control
parameters include the structure or geometry of the solid reactant,
the composition of the solid reactant, and solid reactant surface
modifications. An additional control parameter is in the
environment of the reaction.
Solid Reactant Structure and Geometry
The reason that the solid reactant structure and geometry will
affect the reaction rate of the solid and liquid reactant is
because the structure or geometry affect access between the
reactants. For example, in a preferred embodiment, the solid
reactant is formed into a geometric mass from the powdered
chemical. Rather than having tiny granules or powdered reactant
reacting simultaneously with the liquid reactant, the solid mass
will react only at the surface and additional solid reactant will
become available as only product and gas are formed and the product
is dissolved as the reaction progresses.
Thus, in a preferred embodiment, the solid reactant is formed into
a solid mass. Any geometric shape can be used, although, it is
preferred to choose a shape that will possess a surface area that
provides a substantially constant reaction rate. Thus, spherical,
pyramidal, tetrahedral, cylindrical, rectangular, and like shapes
could all be utilized. Each geometry will provide slightly
different gas generation patterns. In a highly preferred embodiment
of the invention, the solid reactant 10 has a cylindrical shape.
See FIG. 1. This shape is chosen for illustrative purposes because
of its simplicity to prepare. For example, a commercially available
drug tablet press can be utilized. The tablet 13 is preferably
compressed to between 7000 and 8000 psi.
The illustrated embodiment of the solid reactant in FIG. 1 includes
an additional feature that operates to assist in keeping a
substantially constant surface area of the solid reactant in
reactive contact with the liquid reactant. This feature is the bore
11 that extends between the two circular surfaces 12a and 12b in
the solid reactant 10. Gas bubbles, in appropriate circumstances,
can cling to the solid reactant 10 and prevent further reaction
between the liquid reactant and the solid reactant 10. The bore 11
allows generated gas to vent from the lower circular surface 12b
through the solid reactant 10. This assists in keeping the solid
reactant 10 in contact with the liquid reactant.
It will be appreciated, therefore, that a variety of gas generation
profiles are available through varying the geometry or structure of
the solid reactant. The basic profile will be determined,
essentially, by the total surface area in reactive contact with the
liquid reactant and how steadily the surface area changes as the
reaction progresses. The greater the surface area of the solid
reactant in reactive contact with the liquid reactant will
generally cause a faster generation of gas. The smaller the surface
area in reactive contact with the liquid reactant will generally
cause a slower generation of gas. Thereafter, the change in the
surface area of the solid reactant in reactive contact with the
liquid reactant will determine the continued gas generation
profile. Of course, both the size of the solid reactant and its
relative and absolute surface area will affect the gas generation
profile.
The gas generation profile roughly translates into the flow rate
profile as a liquid is driven from a pump. As was mentioned
previously, there is a small correction required for the amount of
gas and its pressure in varying the kinetics of the reaction
between the solid reactant and the liquid reactant.
Solid Reactant Mechanical Properties
As will be appreciated, there are a variety of ways to enhance the
mechanical, physical, and chemical properties of a solid reactant.
One method is to treat or form the solid reactant with chemical
moieties that lend desired properties. In a critical area, it is
desirable for the solid reactant to retain sufficient mechanical
strength so as not to fall apart and lose the ability to enter into
controlled gas generation.
In a preferred embodiment, the solid reactant is surface treated
with a material that enhances its mechanical strength. In a highly
preferred embodiment, for example, where the solid reactant is
sodium carbonate, this can be accomplished through the application
of water to the solid reactant after it has been formed into the
appropriate geometric shape and size. The water forms sodium
carbonate hydrates on at least a portion of the sodium carbonate
solid reactant and creates a tablet with mechanical strength
similar to plaster, yet does not limit the ability of the solid
reactant to participate in the gas generation reaction with the
liquid reactant. In contrast, a tablet made from sodium carbonate
without the application of water results in a solid reactant that
has a propensity to crumble over time and lose its
controllability.
Compositions
In addition to the structure or geometry of the solid reactant, the
composition of the solid reactant can be modified to slow the
dissolution of the solid reactant or slow the rate at which it
becomes accessible to the liquid reactant, which, in turn, slows
the rate at which the solid reactant becomes available for
reaction. Thus, the composition of the solid reactant can be used
to vary the gas generation profile of, and, consequently, the flow
rate profile from, the reaction between the solid reactant and the
liquid reactant.
In a preferred embodiment, the composition of the solid reactant is
modified through the addition of a material that acts to slow the
rate at which solid reactant becomes available for reaction with
the liquid reactant. In another embodiment, the solid reactant is
modified through the addition of a material that acts to slow the
dissolution of the solid reactant. Essentially, such materials each
act to "dilute" the amount of the solid reactant at any one time in
reactive contact with the liquid reactant.
Moieties that can be admixed in the solid reactant and act to
control the reaction rate between the liquid reactant and the solid
reactant are referred to herein as rate controlling moieties. Rate
controlling moieties include fillers and binders. Fillers or
binders are quite effective to slow the reaction rate or limit the
access of the liquid reactant to the solid reactant. Examples of
suitable fillers or binders include polyvinylpyrrolidone (i.e.,
PLASDONE, available from ISP Technologies, Inc., Wayne, N.J.),
polyethylene glycol (i.e., PEG 400 available from Olin Corp.,
Stamford, Conn.), and polyvinyl alcohol (i.e., PVA 205S available
from Air Products, Allentown, Pa.), Ac-Di-Sol.RTM. Goscarmellose
Sodium (cross-linked sodium carboxymethylcellulose) (available from
FMC Corporation, Philadelphia, Pa.). Similarly, there are a large
number of excipients or carriers that will act to slow the chemical
reaction.
Alternatively, as will be appreciated, it is possible to vary the
concentration of the liquid reactant in order to modify the
reaction rate with the solid reactant.
The rate controlling moiety is included in an amount effective to
control the reaction rate between the solid and liquid reactant.
Typically, amounts that are effective to control the reaction rate
are in the range of from about 0.5% to about 50% by weight of the
solid reactant, more preferably from about 1% to about 20% or about
2% to about 15% or about 2.5% to about 7% by weight. In highly
preferred embodiments, the rate controlling moiety is included in
the range of from about 3% to about 6% by weight.
Solid Reactant Surface Modifications
It is also possible to modify the surface of the solid reactant in
order to limit the access of the liquid reactant to the solid
reactant. For example, the solid reactant can be partially coated
with a material that is insoluble in the liquid reactant and that
protects the surface that is coated from reactive contact with the
liquid reactant. Exemplary materials that are useful as insoluble
surface treatments include a room temperature vulcanizing (RTV)
silicone adhesive, such as PERMATEX.RTM., available from Loctite
Corporation, Cleveland, Ohio (Part No. 66B), and a polyurethane
coating (available from B.F. Goodrich).
An example of this strategy is shown in FIG. 2. There, the solid
reactant 10 is coated on its top and bottom surfaces 12a and 12b
with a sealant 13. The sealant 13 prevents the top and bottom
surfaces 12a and 12b of the solid reactant 10 from being dissolved
and reacting with the liquid reactant. In FIG. 3, a partially
reacted solid reactant having the sealant 13 coating the top and
bottom surfaces 12a and 12b is shown in cross-section. The view in
FIG. 3 is taken along line 3--3 in FIG. 2. As will be seen, the
bore 11 has grown in diameter, whereas the diameter of the solid
reactant 10 is reduced. The sealant is still positioned on the
remaining solid reactant 10.
Alternatively, in FIG. 4, the solid reactant 10 is shown with an
sealant applied around the periphery 14. This configuration
requires that the top and bottom surfaces be preferentially
dissolved. In FIG. 5, a partially reacted solid reactant having the
sealant 13 coating the periphery 14 is shown in cross-section. The
view in FIG. 5 is taken along line 5--5 in FIG. 4. As will be seen,
the bore 11 has grown in diameter, whereas the thickness of the
solid reactant 10 is reduced.
In each case, it will be appreciated that the sealant or other
surface modification that causes preferential reaction between a
portion of the solid reactant and the liquid reactant allows
greater control over the generation of gas from the reaction. The
process acts to predictably expose a given surface area of the
solid reactant to the liquid reactant. Accordingly, control is
achieved over the gas generation profile and correspondingly the
flow rate profile of a pump including such reactants with surface
modifications.
An additional surface modification that can be used as an
alternative or additional control on the access of the liquid
reactant to the solid reactant is the utilization of a delayed
reaction coating. In general, a delayed reaction coating in
accordance with the invention is a coating that serves to
temporarily limit or eliminate the exposure of the solid reactant
to the liquid reactant. An object of such limitation is to minimize
any initial effervescence from the reaction of the solid reactant
with the liquid reactant.
One material that can be used with success to achieve such
limitation is a binder or filler, as described above, applied to
the outside of the solid reactant as is shown in FIG. 6. In FIG. 6,
the solid reactant 10 has a layer of coating 15, such as PLASDONE,
applied uniformly over the top and bottom surfaces 12a and 12b. A
thicker layer of the coating 15 is applied to the periphery 14.
Upon mixing the coated solid reactant with the liquid reactant, the
coating 15 on the top and bottom surfaces 12a and 12b will dissolve
more quickly than the coating on the periphery 14. Thus, the gas
generation reaction will be initiated on the top and bottom
surfaces 12a and 12b before the reaction on the periphery 14 is
initiated. In general, the gas generation profile in this reaction
will show a two step increase in the gas generated as first one
surface area of the solid reactant 10 is in reactive contact with
the liquid chemical, followed by an increased surface area in
reactive contact when the coating 15 is dissolved from the
periphery 14. Consequently, the flow rate profile achieved will
begin at a first rate and accelerate to a second rate.
This latter control mechanism can be used in conjunction with the
non-reactive tablet coating, i.e., the sealant described above to
achieve selected gas generation and flow rate profiles.
As will be appreciated, the sealant can be applied in a variety of
patterns, shapes, or contours, any one of which is contemplated in
accordance with the invention. However, for simplicity and for ease
in determining the actual and effective surface area of the solid
reactant that is exposed as well as for purposes of repeatability,
it is often desirable to choose a relatively simple and consistent
pattern and to stay with it.
Reaction Environment
In addition to the above-described modifications that can be
accomplished with respect to the solid and liquid reactants, it is
also possible to enhance the controllability of gas generation
reactions through appropriate selection of the environment in which
the reactions occur. The environmental features that assist in
control over gas generation control are (i) the conduct of the gas
generation reaction within a confined space, wherein the solid
reactant and the liquid reactant are able to stay in reactive
contact regardless of movements of the pump and the like and (ii)
control over the operating pressure that is exerted on the liquid
to be dispensed so as to provide complete control over the flow
rate, regardless of minor fluctuations in the quantity of, or rate
at which the, gas is generated.
In accordance with the present invention, preferably, the gas
generation reaction is conducted within a confined space. One way
that this is accomplished is through the use of a separate gas
generation housing. A device showing a separate gas generating
housing is shown in FIGS. 7 and 8, which is a cross-sectional side
view of an infusion device of the present invention. The device 100
is of a rectangular shape with rounded edges. It is separated into
two separate compartments: the fluid delivery compartment 101 and
the gas generation compartment 102. The fluid delivery compartment
contains the liquid 103, that may contain a medication, that is to
be delivered to a patient. Also within the fluid delivery
compartment is the flexible membrane 104. The flexible membrane 104
is held in proximity to (or distended towards) the outer wall 105
in the lower section of the device 100 by the liquid 103. The
flexible membrane 104 may contact the outer wall 105, or it may
have a slight space 106 (as pictured).
Preferably, the liquid 103 is additionally kept within the fluid
delivery compartment 101, by a one-way valve 107, that generally
has an outer body 108 with an encircled plunger 109. The plunger
109 typically has a proximal end 110 and a distal end 111 (in
relation to the fluid delivery compartment 101). The proximal end
110 of the plunger 109 is typically larger than the distal end 111.
Further, the outer body 108 of the valve 107 has a concentric ridge
112 so that the larger proximal end 110 of the plunger 109 abuts
the ridge 112, preventing the liquid 103 from flowing through the
valve 107. Additionally, the valve 107 can have biasing means, such
a spring 113, that forces the proximal end 110 of the plunger 109
distally toward the ridge 112, thereby further aiding in preventing
the liquid 103 from flowing through the valve 107.
The valve 107 can be specially manufactured or can be a standard
one-way luer fitting, such as those that are commercially
available. For example, the Halkey-Roberts Corporation (St.
Petersburg, Fla.) produces a variety of luer syringe check valves
that can be used for this purpose. We prefer to use Halkey-Roberts
Model No. V24200.
It is preferred that all materials that are in contact with the
liquid 103 in the fluid delivery compartment 101, such as the
flexible membrane 104, the wall 114, and the valve 107 (and it
components) be constructed of materials that are non-leaching and
are appropriate for medical use. One example of such a material is
ultrapure polypropylene and other similar materials. In U.S. Pat.
No. 4,803,102 one formulation of ultrapure polypropylene is
described. Thinner preparations of ultrapure polypropylene (i.e.,
0.002 to 0.010 inch gauge) are used in preparing the flexible
membrane 104 and thicker gauge materials (i.e., molded to 0.030 to
0.060 inch gauge) are preferred for making the casing (defined by
walls 105 and 114). Further, the flexible membrane 104 is
preferably constructed to be gas impermeable, i.e., impermeable to
the gas that is generated in the reaction between the solid
reactant and the liquid reactant described above. In order to
attain gas impermeability in the membrane, either a gas impermeable
material, such as polyvinylindene dichloride or polyether
terephthalate can be used or a composite membrane or bi- or
multi-layer membrane can be prepared. For example, the surface of
the membrane in contact with the liquid 103 in the fluid delivery
compartment 101 can be prepared from ultrapure polypropylene, as
described above, while the surface in communication with the gas
generation compartment 102 can be prepared from polyvinylindene
dichloride or polyether terephthalate.
The gas generating compartment 102 is in fluid communication with
the fluid delivery compartment 101 through a channel 115 and hole
122. Thus, when gas is generated in the gas generating compartment
102 it will travel through the channel 115 either filling or making
the space 106 in the fluid delivery compartment 101. The gas
generating compartment 102 additionally comprises a depressible
membrane 116 which is sealingly joined to the case of the device
100. The depressible membrane sits above the gas generating
compartment 102. Inside the gas generating compartment 102 are the
reactants for generating the gas. Shown in this embodiment is a
liquid reactant 117 that in a preferred embodiment is contained
within a breakable sack 118. Above the sack rests, in this
embodiment, a solid reactant pellet 119.
In a highly preferred embodiment, the liquid reactant 117 is a
solution of citric acid (0.5 gm/ml (2.6M)), i.e., 12 ml, and the
solid reactant is a sodium carbonate "donut shaped" pellet, formed
using a tablet or pill press, of the shape shown in FIG. 1. In the
pellet, preferably 4.39 grams of sodium carbonate is mixed with 5%
by weight of a filler, polyvinylpyrrolidone (PLASDONE, available
from ISP Technologies, Inc., Wayne, N.J.) to make a 4.62 gm pellet.
Moreover, preferably a polyurethane sealant was applied around the
periphery, as shown in FIG. 4, so as to reduce the surface area of
the sodium carbonate and filler that would be exposed to the citric
acid solution.
Also, in this embodiment, the reactants are contained within a
pouch 120. The pouch 120 in a highly preferred embodiment is
composed of a hydrophobic material. Hydrophobic materials generally
will contain liquids but will allow gases to pass, provided, some
of their surface is not covered by the liquid. Hydrophobic
materials are typically formed from polymeric materials. Generally,
they are formed into a membrane. Examples of useful hydrophobic
materials for preparing the pouch 120 are such materials as
Tyvek.RTM. 1073B (Dupont), Versapel.RTM. 450 (Gelman), Goretex.RTM.
0.45.mu. polypropylene bucking, Celguard 2400 (Hoechst-Celanese),
Porex.RTM. (a hydrophobic scintered polypropylene), and 3M BMF.TM.
(Minnesota Mining and Manufacturing).
As will be understood, the use of a hydrophobic pouch 120 is very
useful in that it contains the reactants within the gas generating
chamber 102. This fact reduces concerns that the reactants could
mix with the liquid in the fluid delivery compartment 101. However,
it is critical to note that, as mentioned, the hydrophobic pouch
120 will release gas only so long as a gas pocket 121 exists.
Therefore, the hydrophobic pouch must be carefully designed to
ensure that the gas pocket 121 is maintained throughout the course
of the reaction. If the gas pocket 121 were not present, the pouch
120 would burst and the contents (particularly the liquid reactant
117) of the gas generating compartment 102 would spill into the
fluid delivery compartment 101 through the channel 115 and the hole
122. Since the liquid reactant 117 would no longer be in
substantial contact with the solid reactant 119, the reaction would
essentially terminate and limited additional gas would be evolved.
However, as will be appreciated, because of the generation of gas
through the reaction, there will be a tendency for the pouch 120 to
reinflate and sparge gas, prior to failure.
An additional advantage to the use of the hydrophobic pouch is the
fact that it enables the device 100 to be used in any orientation.
The reactants in the gas generating chamber 102 are physically
separated from the fluid delivery compartment 101 and the liquid
103, and no matter what orientation the device is moved to (so long
as the gas pocket 121 exists) gas will continue to be delivered to
the fluid delivery compartment 101. This makes the device 100 very
versatile. For example, medical personnel do not have to carefully
orient the device 100 and ambulatory patients can carry the device
in their pockets.
It will be appreciated that the advantage associated with the
hydrophobic pouch (i.e., allowing the orientation of the pump to be
an insubstantial consideration since the chemical reactants will
not get near the fluid to be delivered to the patient and allowing
the chemical reactants to stay in contact with one another so as to
continue the chemical reaction therebetween) can be achieved
through a number of other mechanisms. In general, therefore, any
mechanism that allows the gas generated by the reaction between the
reactants to be communicated to the pump while the chemical
reactants remain in contact away from the pump can be used.
Non-limiting examples of such mechanisms include, in addition to
the hydrophobic pouch mentioned above, placing the reactants in a
float or on rollers in a container so that the reactants remain in
the container despite the orientation; use of a hydrophobic
membrane in a lumen in communication with a reactant chamber and a
pump chamber; lining a container, otherwise sealed, with a
hydrophobic material extending above any liquid level and providing
a lumen from the container, behind the hydrophobic material, to
communicate with the pump.
However, returning the embodiment shown in FIG. 8, in order to
operate the pump in this embodiment, a user can simply depress the
depressible membrane 116 down into the gas generating compartment
102 with their index finger, for example. This action will force
the hydrophobic pouch 120 down onto the solid reactant 119. Such
action will break the sack 118 that contained the liquid reactant
117. The chemicals will react and gas will be generated. Provided,
as mentioned above, that the gas pocket 121 is maintained, gas will
flow through the hydrophobic pouch 120 and be communicated through
the hole 122 into the channel 115 and into the fluid delivery
compartment 101. Thereafter, provided that the valve 107 is opened
through manually depressing the distal end 111, proximally, liquid
103 will begin to flow through the valve 107. As gas continues to
be generated the flexible membrane 104 will be displaced away from
wall 105 increasing the size of the space 106 between the wall 105
and the flexible membrane 104 as the liquid 103 is delivered out of
the device 100.
In a preferred embodiment, the hole 122 or the channel 115 comprise
a calibrated orifice. The calibrated orifice is used as the
determining factor in flow rate determination, essentially
establishing a back-pressure against which the device must work to
deliver fluid. It will be appreciated that smaller orifices will
result in higher back pressures and slower flows and larger
orifices will result in reduced back pressures and higher
flows.
As an additional control feature and for safety, a preferred
embodiment of the present invention further includes a pressure
relief valve. A simple, but highly effective, pressure relief valve
is shown in FIGS. 9a and 9b. The pressure relief valve is in
communication with the gas generating chamber through a gas channel
123. The gas channel extends through the casing 125 of the device
into a stem 124 that is topped by a mandrel 126. The mandrel 126 is
topped by an elastomeric material 127 that concentrically and
sealingly surrounds the mandrel 126 as shown in FIG. 9a. The
elastomeric material is essentially similar to a silicone rubber
septum that folds over, surrounds, and seals around the mandrel
126. While the system operates at preferably 10 psi or less, the
elastomeric material 127 will not allow gas to escape. However,
when the system exceeds 10 psi, the gas will force out the sides of
the elastomeric material 127 allowing gas to escape as shown in
FIG. 9b.
We have discovered that use of the pressure relief valve in
combination with the citric acid/sodium carbonate, Plasdone, and
coated pellets, as described above, we can achieve an almost
completely linear pressure profile as is shown in FIG. 10. Such a
linear pressure profile gives rise to an almost perfectly linear
flow rate of fluid from the pump.
It will now also be appreciated that a variety of additional
features could be added to the pressure relief valve of the present
invention in order to lend greater control and conserve gas
pressure. For example, the pressure relief valve shown in FIG. 9
could be replaced by a balloon or other pressure/gas reserve
mechanism. There are, for instance, inelastic balloon structures
that do not show enhanced pressure at reduced diameters. Such
materials could be attached to the mandrel 126 in FIG. 9 to capture
excess gas. As well, simple two way regulators can be readily
conceived of by those of ordinary skill in the art to remove excess
gas at a given pressure from the system and introduce gas back to
the system when the pressure falls below a certain, predetermined
pressure.
As will now be seen, the conduct of the reaction within a confined
space and the use of a pressure relief valve are significant in
adding yet another degree of control to the generation of gas in
accordance with the invention. Where a pressure relief valve is
utilized, it is important that sufficient quantities of reactants
be used in order that the sparging of any excess gas does not end
the reaction before all of the liquid is dispensed from the pump.
Accordingly, in a preferred embodiment, sufficient quantities of
reactants are included to sustain the generation of gas for a
period of time that is effective to dispense substantially all of
the fluid from the pump.
As will now be appreciated, through the use of a pressure relief
valve, in theory, an otherwise uncontrolled reaction can be used to
attain a substantially constant flow rate from the pump.
As will also now be appreciated, confining of the reactants does
not necessarily have to be accomplished in a different physical
space. For example, the reactants may be separately disposed into a
hydrophobic pouch, as described above, and placed anywhere where
the gas emerging therefrom would expand a membrane and cause a
liquid to be dispensed from a pump. This brings to thought that
prior art devices can be easily modified in accordance with the
structural teachings of the present invention to enable the
attainment of substantially constant flow rates, which was
previously not possible.
Quantity of Reactants for Attainment of Specific Flow Rates
In order to tailor devices prepared in accordance with the present
invention to particular applications, it is preferable that a user
or designer establish a minimum and maximum of reactants that will
be necessary to attain a given flow rate over a given period of
time. It will be appreciated that in certain infusion applications
it is preferable to have relatively low flow rates, whereas in
other applications relatively higher flow rates are preferable.
Pumps prepared in accordance with the present invention can be
prepared to generate flow rates from as low or lower than 2 ml. per
hour to upwards of 200 ml. per hour. Particularly preferred flow
rates are in the range of from about 5, 10, 15, 20, 50, 100, 150,
or 200 ml. per hour. Therefore, a pump can be prepared with
sufficient chemical reactants to allow only a fluid flow rate of 5
or 10 ml. per hour. Or, the pumps can be similarly prepared to
provide a flow rate of 150 or 200 ml. per hour.
To attain any particular rates, a flow rate profile should be
settled upon. The flow rate profile will govern the tablet or solid
reactant design, including, the use of fillers, non-reactive skin
modifications, delayed reaction coatings, and tablet size and
geometry. In connection with consideration of the flow rate
profile, the desired start-up speed (i.e., the rate at which the
gas generation reaction attains static operating pressure), the
length of the delivery that is required and the quantity that is
required to be delivered during the time period (i.e., 10 ml./hr.
for 20 hours versus 20 ml./hr. for 10 hours; in each instance
requiring delivery of 200 ml but in different time periods), and
any additional factors, such as flow rate steps and the like,
should be considered.
As an additional consideration, as mentioned above, in order to
attain particular flow rates, a calibrated orifice is utilized to
attain a particular flow rate under particular reaction
conditions.
Once the above-essential elements are determined, a user can
extrapolate the required amounts of reactants from the following
table:
TABLE II ______________________________________ Sodium Carbonate
Maximum (shape: Citric Seal- Reaction Accurate FIG. 1) Acid Filler
ant Length Flow Rate ______________________________________ 5.25 gm
5.00 gm 0.25 gm Yes 120 min 200 ml/hr 5.25 gm 5.00 gm 0.20 gm Yes
70 min 200 ml/hr 5.25 gm 4.00 gm 0.23 gm Yes 70 min 100 ml/hr 4.50
gm 5.00 gm 0.25 gm Yes 100 min 200 ml/hr 4.50 gm 4.50 gm 0.23 gm
Yes 90 min 200 ml/hr 4.00 gm 4.00 gm 0.25 gm Yes 65 min 100 ml/hr
4.00 gm 4.00 gm 0.20 gm Yes 60 min 100 ml/hr
______________________________________
Alternatively, a user can perform certain empirical tests to
determine the necessary operating conditions for a particular
application. Such experiments can be run as described below:
Reaction Length
Side-by-side tests can be run with tablets constructed in
accordance with FIG. 2 having varying quantities of solid and
liquid reactants and binders in containers (i.e., erlenmeyer
flasks) which are closed after the reaction is initiated with a
one-hole stopper having a tube running into individual upside down
beakers filled with, and in a pool of, water. The gas generated in
the reaction will displace the water from the beaker and the time
for the complete reaction can be measured to give the reaction
length.
Flow Rate
Once the reaction length is known for a chosen composition, a
general flow rate can be readily determined through measuring the
length of time required to displace a given quantity of liquid. For
example, a graduated cylinder can be filled with, and placed upside
down in a pool of, water and displacement can be measured as
described for reaction length.
* * * * *